A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/ß-catenin pathways for treatment of AML with high PRL-3 phosphatase.
J Hematol Oncol
; 11(1): 36, 2018 03 07.
Article
en En
| MEDLINE
| ID: mdl-29514683
ABSTRACT
BACKGROUND:
Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor.METHODS:
In this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients. AML mouse xenograft model was used to examine the in vivo synergism.RESULTS:
The list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/ß-catenin pathway and AKT/mTOR signaling. These findings prompted us to explore the impact of AKT/mTOR signaling inhibition in PRL-3 high AML cells in combination with WNT/ß-catenin inhibitor. VS-5584, a novel, highly selective dual PI3K/mTOR inhibitor, and ICG-001, a WNT inhibitor, were used as a combination therapy. A synthetic lethal interaction between mTOR/AKT pathway inhibition and WNT/ß-catenin was validated by a variety of cellular assays. Notably, we found that treatment with these two drugs significantly reduced leukemic burden and prolonged survival of mice transplanted with human PRL-3 high AML cells, but not with PRL-3 low AML cells.CONCLUSIONS:
In summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/ß-catenin pathways in PRL-3 high AML cells. Simultaneous inhibition of these two pathways could achieve robust clinical efficacy for this subtype of AML patient with high PRL-3 expression and warrant further clinical investigation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
/
Pruebas Genéticas
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Proteínas Tirosina Fosfatasas
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Proteínas Proto-Oncogénicas c-akt
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Beta Catenina
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Serina-Treonina Quinasas TOR
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Vía de Señalización Wnt
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Proteínas de Neoplasias
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Hematol Oncol
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2018
Tipo del documento:
Article
País de afiliación:
Singapur